Parasitic nematodes infect one in four human beings, causing frank illness and retarded physical and cognitive development in hundreds of millions. In order to find, contact and infect the host, the invasive stages of these parasites must receive and process a variety of sensory cues from their physical and biological environments, including the host itself. Moreover, the human parasite Strongyloides stercoralis is unique in its ability to undergo fulminant autoinfection in which progeny of parasitic females develop rapidly to infectivity, penetrate the gut wall and invade the tissues of their primary host. Unregulated autoinfection can bring about geometric expansion of the parasite population, resulting in overwhelming, potentially fatal disease. The overall goal of this project is to understand the roles of sensory neurons and neuronal networks in regulating the infective process in parasitic nematodes generally. The research plan comprises three specific aims: 1.) to elucidate neuronal control of key steps in the infective process in S. stercoralis infection. Here, ablation by laser microbeam will be used to test hypotheses that specific neurons control behaviors such as negative geotaxis, chemotaxis towards molecules from the host skin and initiation of parasitic development. 2.) To reconstruct the sensory neuroanatomy of the parasitic nematode Parastrongyloides trichosuri; compare it to C. elegans and to more or less closely related parasitic nematodes. P. trichosuri has a distinct advantage over previously used models in that it can be reared in vitro as a free-living organism while remaining capable of infecting a host via a program of development and migration that is common in obligate parasites. Anticipating that it will be used increasingly as a model for basic research, it is crucial to confirm the similarity of P. trichosuri's sensory neuroanatomy and function to other free-living and parasitic nematodes. 3.) To seek molecular markers for specific amphidial neurons of S. stercoralis. This work will establish a third criterion, in addition to anatomical position and function, for establishing homologies between sensory neurons in parasitic nematodes and C. elegans. We will also explore the use of transgene constructs containing neuron- specific promoters coupled to mutant channel forming proteins as tools for genetic ablation of sensory neurons, and possibly other types of cells in S. stercoralis and other parasitic nematodes. Though underappreciated by the medical establishments of developed nations, parasitic nematodes cause disease in almost half a billion persons living primarily in developing countries. Some of the most important of these pathogens, hookworms and threadworms, infect their hosts via the per-cutaneous route. We propose to continue with a program of research aimed at understanding the neuronal control of key behaviors associated with the infective process in the threadworm Strongyloides stercoralis and a related parasite Parastrongyloides trichosuri, seeking for the first time to take our studies to the molecular level, thereby providing a rational framework for the discovery of new drug targets that could interfere with this process.